1 6881 98 [RESEARCH PROGRESS OF M6A METHYLATION MODIFICATION IN HEMATOLOGICAL TUMORS--REVIEW]. N6-METHYLADENOSINE (M6A) IS ONE OF THE MOST COMMON EPIGENETIC MODIFICATIONS OF EUKARYOTIC MRNAS, WHICH IS INVOLVED IN THE REGULATION OF GENE EXPRESSIONS AND BIOLOGICAL PROCESSES IN A VARIETY OF CELLS WITH DYNAMIC AND REVERSIBLE METHYLATION PROCESSES. IN RECENT YEARS, MANY STUDIES HAVE SHOWN THAT M6A METHYLATION MODIFICATION NOT ONLY ACTS ON THE GROWTH, PROLIFERATION, AND MEDULLARY DIFFERENTIATION OF ACUTE MYELOID LEUKEMIA CELLS, BUT ALSO PARTICIPATES IN THE REGULATION OF THE PROLIFERATION AND APOPTOSIS OF OTHER HEMATOLOGICAL TUMOR CELLS SUCH AS CHRONIC MYELOID LEUKEMIA AND DIFFUSE LARGE B-CELL LYMPHOMA, AND IT CAN EVEN WEAKEN THE EFFICACY OF ANTI-HEMATOLOGICAL TUMOR IMMUNOTHERAPY AND INDUCE IMMUNE ESCAPE LEADING TO TUMOR RESISTANCE. WITH THE SUCCESSIVE DEVELOPMENT OF A VARIETY OF M6A METHYLATION-RELATED ENZYME INHIBITORS, IT WILL PROVIDE NEW THERAPEUTIC IDEAS FOR PATIENTS WITH RELAPSED AND REFRACTORY HEMATOLOGICAL TUMORS. IN THIS PAPER, WE REVIEW THE RESEARCH PROGRESS ON THE MECHANISM OF M6A METHYLATION ON THE OCCURRENCE, DEVELOPMENT, AND TUMOR IMMUNITY OF VARIOUS HEMATOLOGICAL TUMORS. 2022 2 6773 34 [ADVANCES OF RESEARCH ON DEMETHYLATION THERAPY FOR HEMATOLOGIC MALIGNANCIES]. DNA METHYLATION IS AN IMPORTANT AND REVERSIBLE EPIGENETIC MODIFICATION WHICH REGULATES GENOMIC STABILITY. METHYLATION IS ESSENTIAL FOR MAMMALIAN DEVELOPMENT. GENERALLY, GENE EXPRESSION LEVEL AND DNA METHYLATION ARE NEGATIVE CORRELATION. TRANSCRIPTIONAL SILENCING VIA METHYLATION OF CPG ISLANDS IN THE PROMOTER IS IMPORTANT FOR CELL GROWTH AND DIFFERENTIATION AND PLAYS A KEY ROLE IN TUMORIGENESIS. DEMETHYLATION DRUG CAN MODIFY CHROMATIN AND RESTORE THE ABILITY OF ANTI-ONCOGENE. DEMETHYLATION THERAPY AS A NEW THERAPY MAY TREAT EFFICIENTLY HEMATOLOGICAL MALIGNANCIES WITH RESISTANCE AND RELAPSE. IN THIS REVIEW, DNA METHYLATION MECHANISM, RELATIONSHIP BETWEEN ABERRANT METHYLATION AND HEMATOLOGIC MALIGNANCIES, MECHANISM OF DEMETHYLATION THERAPY, THE ADVANCE OF RESEARCH ON THE DEMETHYLATION THERAPY OF HEMATOLOGICAL MALIGNANCIES, SUCH AS ACUTE AND CHRONIC LEUKEMIA, LYMPHOMA, MYELODYSPLASTIC SYNDROME WERE SUMMARIZED. 2009 3 1542 35 DNA METHYLATION IN HAEMATOLOGICAL MALIGNANCIES: THE ROLE OF DECITABINE. NORMAL CELL DEVELOPMENT AND FUNCTION IS DEPENDENT UPON CONTROLLED GENE EXPRESSION. DNA METHYLATION IS AN EPIGENETIC MODIFICATION THAT CAN PLAY AN IMPORTANT ROLE IN THE CONTROL OF GENE EXPRESSION. DNA METHYLATION AT CYTOSINE RESIDUES IN GENE PROMOTER CPG SEQUENCES IS KNOWN TO INHIBIT GENE TRANSCRIPTION. INAPPROPRIATE INHIBITION OF THE TRANSCRIPTION OF TUMOUR SUPPRESSOR GENES, GENES THAT INHIBIT ANGIOGENESIS AND METASTASIS AND GENES INVOLVED IN DNA REPAIR BY UNCONTROLLED METHYLATION, CAN LEAD TO UNREGULATED GROWTH AND PROLIFERATION OF A CELL AND CARCINOGENESIS. PROMOTER HYPERMETHYLATION AFFECTING THE P16 GENE, RESULTING IN GENE SILENCING, HAS BEEN SHOWN TO OCCUR IN MANY HUMAN SOLID TUMOURS AND A 'HYPERMETHYLATION PROFILE' IN SOME LEUKAEMIAS HAS BEEN DEFINED. THE MOLECULAR MECHANISMS BY WHICH ABERRANT DNA METHYLATION TAKES PLACE DURING CARCINOGENESIS ARE STILL NOT CLEAR. HOWEVER, THE LARGE NUMBER OF TARGET GENES (INVOLVED IN TUMORIGENESIS) THAT ARE SILENCED BY ABERRANT METHYLATION SUGGESTS THAT INHIBITION OF THIS PROCESS MAY HAVE POTENTIAL AS CANCER THERAPY. DECITABINE (NSC-127716, DACOGEN; SUPERGEN) IS A POTENT AND SPECIFIC HYPOMETHYLATING AGENT AND AN INHIBITOR OF THE DNA METHYLTRANSFERASE ACTIVITY THAT MEDIATES DNA METHYLATION. DECITABINE HAS BEEN SHOWN TO HAVE A BROAD RANGE OF ANTINEOPLASTIC ACTIVITY IN PRECLINICAL STUDIES. THIS AGENT HAS EXHIBITED SIGNIFICANT ACTIVITY IN THE TREATMENT OF PATIENTS WITH MYELODYSPLASTIC SYNDROME, CHRONIC MYELOID LEUKAEMIA AND ACUTE MYELOID LEUKAEMIA, ALTHOUGH CLINICAL PHASE I AND II STUDIES WITH SOLID TUMOURS HAVE NOT BEEN VERY PROMISING. PHASE II AND III STUDIES ARE CURRENTLY ONGOING TO EVALUATE DECITABINE, BOTH ALONE AND IN COMBINATION, IN VARIOUS STAGES OF THESE HAEMATOLOGICAL MALIGNANCIES. 2003 4 6371 44 THE ROLE OF MICRORNAS IN THE PATHOGENESIS AND TREATMENT OF HEMATOPOIETIC MALIGNANCIES. MICRORNAS (MIRNAS) COMPRISE A RECENTLY DISCOVERED CLASS OF NON-CODING RNAS WITH REGULATORY FUNCTIONS IN POST-TRANSCRIPTIONAL GENE EXPRESSION CONTROL. MANY MIRNAS ARE LOCATED IN GENOMIC REGIONS THAT ARE FREQUENTLY DELETED IN CANCER, OR ARE SUBJECT TO EPIGENETIC AND TRANSCRIPTIONAL DEREGULATION IN CANCER CELLS. THE MIRNA TRANSCRIPTOME OF CANCER CELLS IS VERY DIFFERENT FROM THAT OF THEIR NORMAL CELL COUNTERPARTS. MIRNAS CAN EXHIBIT ONCOGENIC OR TUMOR SUPPRESSIVE OR EVEN BOTH PROPERTIES DEPENDING ON THE SPECIFIC TARGETS AND CELLULAR CONTEXT. IT IS BECOMING INCREASINGLY CLEAR THAT MIRNAS NOT ONLY SERVE AS USEFUL TUMOR BIOMARKERS WITH IMPLICATIONS FOR DIAGNOSIS, PROGNOSIS AND THE PREDICTION OF TREATMENT RESPONSES, BUT MAY ALSO BE USED FOR TARGETED CANCER TREATMENT AND EVEN AS THERAPEUTICS. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF RECENT ADVANCES IN OUR UNDERSTANDING OF THE TUMOR SUPPRESSOR MIRNAS AND ONCOMIRS INVOLVED IN THE PATHOGENESIS OF LEUKEMIAS AND LYMPHOMAS, AND THEIR TARGET TRANSCRIPTS IN CANCER SIGNALING NETWORKS. IN PARTICULAR, WE FOCUS ON THE ROLE OF MIRNAS IN CHRONIC LYMPHOCYTIC AND ACUTE LYMPHOBLASTIC LEUKEMIA AND IN B-CELL LYMPHOMAS. IN THE SECOND PART, WE REVIEW THE VARIOUS ALTERNATIVE STRATEGIES OF TARGETING MIRNAS IN CANCER THERAPY. METHODS OF ONCOMIR ANTAGONIZATION BY ANTAGOMIRS OR LOCKED NUCLEID ACIDS ARE CONTRASTED WITH STRATEGIES THAT HARNESS THE TUMOR SUPPRESSIVE PROPERTIES OF CERTAIN MIRNAS FOR CANCER TREATMENT. PRECLINICAL PROGRESS, ALSO WITH REGARD TO DELIVERY STRATEGIES, POSSIBLE SIDE EFFECTS AND OTHER PHARMACOLOGICAL ASPECTS, IS PRESENTED ALONG WITH RESULTS FROM THE FIRST HUMAN TRIALS ASSESSING THE SAFETY AND EFFICACY OF MIRNA-TARGETING THERAPEUTICS. 2013 5 358 32 ALTERNATIVE SPLICING IN CHRONIC MYELOID LEUKEMIA (CML): A NOVEL THERAPEUTIC TARGET? ALTHOUGH THE IMATINIB BASED THERAPY OF CHRONIC MYELOID LEUKEMIA (CML) REPRESENTS A TRIUMPH OF MEDICINE, NOT ALL PATIENTS WITH CML BENEFIT FROM THIS DRUG DUE TO THE DEVELOPMENT OF RESISTANCE AND INTOLERANCE. THE INTERRUPTION OF IMATINIB TREATMENT IS OFTEN FOLLOWED BY CLINICAL RELAPSE, SUGGESTING A FAILURE IN THE KILLING OF RESIDUAL LEUKAEMIC STEM CELLS. THERE IS NEED TO IDENTIFY ALTERNATIVE SELECTIVE MOLECULAR TARGETS FOR THIS DISEASE AND DEVELOP MORE EFFECTIVE THERAPEUTIC APPROACHES. ALTERNATIVE PRE-MRNA SPLICING (AS) IS AN EPIGENETIC PROCESS THAT GREATLY DIVERSIFIES THE REPERTOIRE OF THE TRANSCRIPTOME. AS ORCHESTRATES INTERACTIONS BETWEEN VARIOUS TYPES OF PROTEINS AND BETWEEN PROTEINS AND NUCLEIC ACIDS. CHANGES CAUSED BY INDIVIDUAL SPLICING EVENTS IN THE CELLS ARE SMALL, HOWEVER, "SPLICING PROGRAMS" TYPICALLY REACT TO THESE INDIVIDUAL CHANGES WITH CONSIDERABLE EFFECTS IN CELL PROLIFERATION, CELL SURVIVAL, AND APOPTOSIS. CURRENT EVIDENCE SUGGESTS A PIVOTAL ROLE OF AS IN LEUKEMIAS, PARTICULARLY IN MYELODISPLASTIC SYNDROME (MDS) AND CHRONIC LYMPHOCYTE LEUKEMIA (CLL). FROM THESE STUDIES AND STUDIES IN OTHER MALIGNANCES, IT IS CLEAR THAT SPLICING ABNORMALITIES PLAY A SIGNIFICANT ROLE IN MALIGNANT TRANSFORMATION. EVALUATION OF AS EVENTS IN CML CAN BE USED TO IDENTIFY NOVEL DISEASE MARKERS AND DRUGSENSITIVE TARGETS TO OVERCOME THE LIMITS OF THE SMALL MOLECULE INHIBITORS CURRENTLY USED FOR TREATING PATIENTS WITH CML. THE USE OF ABERRANT SPLICE VARIANTS AS DISEASE MARKERS HAS BEEN REPORTED, HOWEVER, LITTLE IS KNOWN ABOUT THE USE OF SPLICING ABNORMALITIES AS DRUG TARGETS IN CML. HEREIN WE DISCUSS POTENTIAL THERAPEUTIC APPROACHES THAT CAN BE USED TO TARGET SPLICING ABNORMALITIES IN CML. 2013 6 2652 37 EPIGENOMICS OF LEUKEMIA: FROM MECHANISMS TO THERAPEUTIC APPLICATIONS. LEUKEMOGENESIS IS A MULTISTEP PROCESS IN WHICH SUCCESSIVE TRANSFORMATIONAL EVENTS ENHANCE THE ABILITY OF A CLONAL POPULATION ARISING FROM HEMATOPOIETIC PROGENITOR CELLS TO PROLIFERATE, DIFFERENTIATE AND SURVIVE. CLINICALLY AND PATHOLOGICALLY, LEUKEMIA IS SUBDIVIDED INTO FOUR MAIN CATEGORIES: CHRONIC LYMPHOCYTIC LEUKEMIA, CHRONIC MYELOID LEUKEMIA, ACUTE LYMPHOCYTIC LEUKEMIA AND ACUTE MYELOID LEUKEMIA. LEUKEMIA HAS BEEN PREVIOUSLY CONSIDERED ONLY AS A GENETIC DISEASE. HOWEVER, IN RECENT YEARS, SIGNIFICANT ADVANCES HAVE BEEN MADE IN THE ELUCIDATION OF THE LEUKEMOGENESIS-ASSOCIATED PROCESSES. THUS, WE HAVE COME TO UNDERSTAND THAT EPIGENETIC ALTERATIONS INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS AND MIRNA ARE INVOLVED IN THE PERMANENT CHANGES OF GENE EXPRESSION CONTROLLING THE LEUKEMIA PHENOTYPE. IN THIS ARTICLE, WE WILL FOCUS ON THE EPIGENETIC DEFECTS ASSOCIATED WITH LEUKEMIA AND THEIR IMPLICATIONS AS BIOMARKERS FOR DIAGNOSTIC, PROGNOSTIC AND THERAPEUTIC APPLICATIONS. 2011 7 5549 24 ROLE OF EPIGENETICS IN CHRONIC MYELOID LEUKEMIA. THE EFFICACY OF THERAPEUTIC MODALITIES IN CHRONIC MYELOID LEUKEMIA (CML) DEPENDS ON BOTH GENETIC AND EPIGENETIC MECHANISMS. THIS REVIEW FOCUSES ON EPIGENETIC MECHANISMS INVOLVED IN THE PATHOGENESIS OF CML AND IN RESISTANCE OF TUMOR CELLS TO TYROSINE KINASE INHIBITORS LEADING TO THE LEUKEMIC CLONE ESCAPE AND PROPAGATION. REGULATORY EVENTS AT THE LEVELS OF GENE REGULATION BY TRANSCRIPTION FACTORS AND MICRORNAS ARE DISCUSSED IN THE CONTEXT OF CML PATHOGENESIS AND THERAPEUTIC MODALITIES. 2013 8 160 35 ABERRANT PROMOTER HYPOMETHYLATION IN CLL: DOES IT MATTER FOR DISEASE DEVELOPMENT? OVER THE LAST 30 YEARS, STUDIES OF ABERRANT DNA METHYLATION IN HEMATOLOGIC MALIGNANCIES HAVE BEEN DOMINATED BY THE PRIMARY FOCUS OF UNDERSTANDING PROMOTER HYPERMETHYLATION. THESE EFFORTS NOT ONLY RESULTED IN A BETTER UNDERSTANDING OF THE BASIS OF EPIGENETIC SILENCING OF TUMOR SUPPRESSOR GENES BUT ALSO RESULTED IN APPROVAL OF HYPOMETHYLATING AGENTS FOR THE TREATMENT OF SEVERAL MALIGNANCIES, SUCH AS MYELODYSPLASTIC SYNDROME AND ACUTE MYELOID LEUKEMIA. RECENT ADVANCES IN GLOBAL METHYLATION PROFILING COUPLED WITH THE USE OF MOUSE MODELS SUGGEST THAT ABERRANT PROMOTER HYPOMETHYLATION IS ALSO A FREQUENT EVENT IN HEMATOLOGIC MALIGNANCIES, PARTICULARLY IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). PROMOTER HYPOMETHYLATION AFFECTS GENE EXPRESSION AND, THEREFORE, MAY PLAY AN IMPORTANT ROLE IN DISEASE PATHOGENESIS. HERE, WE REVIEW RECENT FINDINGS AND DISCUSS THE POTENTIAL INVOLVEMENT OF ABERRANT PROMOTER HYPOMETHYLATION IN CLL. 2016 9 6896 27 [TARGETED EPIGENETIC THERAPY OF CANCER. ACHIEVEMENTS AND PERSPECTIVES]. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF THE PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL EPIGENETIC CHANGES OF NORMAL CELLS AND CANCER CELLS, AND EMPHASIZE THE ACHIEVEMENTS AND THE PERSPECTIVES OF CANCER EPIGENETIC THERAPY. CANCER EPIGENETIC ALTERATIONS CORRESPOND FOREMOST TO HYPERMETHYLATION OF TUMOR SUPPRESSOR GENES PROMOTORS, GLOBAL DNA HYPOMETHYLATION, AND OVEREXPRESSION AND ACTIVITY OF HISTONE DEACETYLASES. THE PURPOSE OF EPIGENETIC THERAPY IS TO REVERT THE EPIGENETIC ALTERATIONS IN CANCER CELLS AND OBTAIN THE "NORMAL EPIGENOME" RESTORATION. EPIGENETIC TARGETS IN CANCER THERAPY HAVE FOCUSED ON HDACS AND DNMTS INHIBITION. THE AZACITIDINE AND THE DECITABINE, THE VORINOSTAT AND THE ROMIDEPSIN WERE APPROVED BY US-FDA FOR TREATMENT OF MYELODYSPLASTIC SYNDROME, AND CUTANEOUS T-CELL LYMPHOMA, RESPECTIVELY. EPIGENETIC AND EPIGENOMIC CHANGES IN SINGLE OR MULTIPLE GENES HAVE SHOWED POTENTIAL IMPACT IN CANCER AS EARLY DETECTION, PROGNOSIS AND PREDICTIVE MARKS. THE EPIGENETIC REVOLUTION HAS ARRIVED FOR BIOLOGY. THE SIGNIFICANT PROGRESS IN EPIGENETIC STUDIES HAVE ALLOWED US, TO UNDERSTAND NEW LOOKS IN THE PHYSIOLOGY AND PATHOPHYSIOLOGY OF EMBRYONIC DEVELOPMENT, CANCER AND OTHER CHRONIC DISEASES. SPECIFIC MOLECULAR EPIGENETIC ALTERATIONS IN DIFFERENT CANCER TYPES, GIVE US NEW STRATEGIES TO DESIGN IMPROVED CANCER THERAPY. THE CHALLENGE FOR EPIGENETIC INVESTIGATORS IS DESIGN MORE SPECIFIC EPIDRUGS WITH LESSER SIDE EFFECTS. 2012 10 1568 28 DNA METHYLATION OF TUMOR-SUPPRESSOR MIRNA GENES IN CHRONIC LYMPHOCYTIC LEUKEMIA. DNA METHYLATION IS ONE OF THE MOST IMPORTANT EPIGENETIC MODIFICATIONS OF THE GENOME INVOLVED IN THE REGULATION OF NUMEROUS CELLULAR PROCESSES THROUGH GENE SILENCING WITHOUT ALTERING DNA SEQUENCES. MIRNAS, A CLASS OF SINGLE-STRANDED NONCODING RNAS OF 19-25 NUCLEOTIDES IN LENGTH, FUNCTION AS POST-TRANSCRIPTIONAL REGULATORS OF GENE EXPRESSION LEADING TO MRNA CLEAVAGE OR TRANSLATIONAL REPRESSION OF THEIR CORRESPONDING TARGET PROTEIN-CODING GENES. RECENTLY, DYSREGULATION OF TUMOR SUPPRESSOR MIRNAS MEDIATED BY PROMOTER DNA HYPERMETHYLATION IS IMPLICATED IN HUMAN CANCERS, INCLUDING B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). MOREOVER, IT APPEARS THAT METHYLATED MIRNA GENES COULD BE POTENTIAL BIOMARKERS FOR CLL DIAGNOSIS OR THERAPY. THIS REVIEW WILL HIGHLIGHT THE ROLE OF ABERRANT METHYLATION OF MIRNA GENES IN THE PATHOGENESIS OF CLL. 2015 11 6326 23 THE ROLE OF BCL-2 FAMILY PROTEINS IN CHRONIC LYMPHOCYTIC LEUKAEMIA. BCL-2 FAMILY PROTEINS HAVE LONG BEEN IMPLICATED IN THE PATHOLOGY OF CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL). INDEED, A NUMBER OF THESE PROTEINS HAVE BEEN SHOWN TO HAVE PROGNOSTIC IMPORTANCE IN THIS DISEASE. THE PRECISE WAYS IN WHICH THESE PROTEINS IMPACT UPON CLL AND THE WAYS IN WHICH THEY ARE REGULATED REMAIN INCOMPLETELY RESOLVED. HOWEVER, SIGNIFICANT ADVANCES HAVE BEEN RECENTLY MADE IN OUR UNDERSTANDING OF HOW THESE PROTEINS ARE CONTROLLED BY GENETIC, EPIGENETIC AND MICROENVIRONMENTAL CUES. FURTHERMORE, MAJOR PROGRESS HAS BEEN MADE IN TRYING TO TARGET THESE PROTEINS THERAPEUTICALLY. HERE WE REVIEW THE CURRENT KNOWLEDGE ABOUT THIS FAMILY OF APOPTOSIS-REGULATING PROTEINS AND HOW THEY IMPACT UPON DRUG RESISTANCE AND DISEASE PROGRESSION. WE ALSO SUMMARISE EVOLUTION IN THE DEVELOPMENT OF BCL-2 FAMILY INHIBITORS FOR THE TREATMENT OF CLL AND OTHER CANCERS. 2010 12 209 34 ACTIVATION-INDUCED CYTIDINE DEAMINASE: IN SICKNESS AND IN HEALTH. ACTIVATION INDUCED CYTIDINE DEAMINASE (AID) IS AN ESSENTIAL ENZYME OF THE ADAPTIVE IMMUNE SYSTEM. ITS CANONICAL ACTIVITY IS RESTRICTED TO B LYMPHOCYTES, PLAYING AN ESSENTIAL ROLE IN THE DIVERSIFICATION OF ANTIBODIES BY ENHANCING SPECIFICITY AND CHANGING AFFINITY. THIS IS POSSIBLE THROUGH ITS DNA DEAMINASE FUNCTION, LEADING TO MUTATIONS IN DNA. IN THE LAST DECADE, AID HAS BEEN ASSIGNED AN ADDITIONAL FUNCTION: THAT OF A POWERFUL DNA DEMETHYLATOR. ADVERSE CELLULAR CONDITIONS SUCH AS CHRONIC INFLAMMATION CAN LEAD TO ITS DEREGULATION AND OVEREXPRESSION. IT IS AN IMPORTANT DRIVER OF B-CELL LYMPHOMA DUE TO ITS NATURAL ABILITY TO MODIFY DNA THROUGH DEAMINATION, LEADING TO MUTATIONS AND EPIGENETIC CHANGES. HOWEVER, THE DEREGULATION OF AID IS NOT RESTRICTED TO LYMPHOID CELLS. RECENT FINDINGS HAVE PROVIDED NEW INSIGHTS INTO THE ROLE THAT THIS PROTEIN PLAYS IN THE DEVELOPMENT OF NON-LYMPHOID CANCERS, WITH SOME RESEARCH SHEDDING LIGHT ON NOVEL AID-DRIVEN MECHANISMS OF CELLULAR TRANSFORMATION. IN THIS REVIEW, WE PROVIDE AN UPDATED NARRATIVE OF THE NORMAL PHYSIOLOGICAL FUNCTIONS OF AID. ADDITIONALLY, WE REVIEW AND DISCUSS THE RECENT RESEARCH STUDIES THAT HAVE IMPLICATED AID IN CARCINOGENESIS IN VARYING TISSUE TYPES INCLUDING LYMPHOID AND NON-LYMPHOID CANCERS. WE REVIEW THE MECHANISMS, WHEREBY AID PROMOTES CARCINOGENESIS AND HIGHLIGHT IMPORTANT AREAS OF FUTURE RESEARCH. 2020 13 4693 26 NEXT GENERATION OF TARGETED MOLECULES FOR NON-HODGKIN LYMPHOMAS: SMALL-MOLECULE INHIBITORS OF INTRACELLULAR TARGETS AND SIGNALING PATHWAYS. ADVANCES IN OUR UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF B-CELL LYMPHOMA HAVE GUIDED THE DEVELOPMENT OF TARGETED THERAPIES THAT DISRUPT ABERRANT SIGNALING PATHWAYS IMPORTANT FOR COMMUNICATION WITHIN LYMPHOMA CELLS AND FOR THEIR INTERACTIONS WITH THE TUMOR MICROENVIRONMENT. THIS HAS LED TO UNPRECEDENTED THERAPEUTIC PROGRESS, WITH BIOLOGIC AGENTS THAT HAVE BEGUN TO TRANSFORM THE CARE OF PATIENTS WITH LYMPHOMA AND CHRONIC LYMPHOCYTIC LEUKEMIA. THIS REVIEW DISCUSSES THE MECHANISMS OF ACTION, CLINICAL DEVELOPMENT, AND EMERGING APPLICATIONS OF SMALL-MOLECULE INHIBITORS THAT TARGET B-CELL RECEPTOR SIGNALING PATHWAYS, B-CELL LYMPHOMA-2 INHIBITORS, SELECTIVE INHIBITORS OF NUCLEAR EXPORT, AND EPIGENETIC MODIFIERS. 2016 14 1232 37 CROSSTALK BETWEEN INFLAMMATORY SIGNALING AND METHYLATION IN CANCER. INFLAMMATION IS AN INTRICATE IMMUNE RESPONSE AGAINST INFECTION AND TISSUE DAMAGE. WHILE THE INITIAL IMMUNE RESPONSE IS IMPORTANT FOR PREVENTING TUMORIGENESIS, CHRONIC INFLAMMATION IS IMPLICATED IN CANCER PATHOGENESIS. IT HAS BEEN LINKED TO VARIOUS STAGES OF TUMOR DEVELOPMENT INCLUDING TRANSFORMATION, PROLIFERATION, ANGIOGENESIS, AND METASTASIS. IMMUNE CELLS, THROUGH THE PRODUCTION OF INFLAMMATORY MEDIATORS SUCH AS CYTOKINES, CHEMOKINES, TRANSFORMING GROWTH FACTORS, AND ADHESION MOLECULES CONTRIBUTE TO THE SURVIVAL, GROWTH, AND PROGRESSION OF THE TUMOR IN ITS MICROENVIRONMENT. THE ABERRANT EXPRESSION AND SECRETION OF PRO-INFLAMMATORY AND GROWTH FACTORS BY THE TUMOR CELLS RESULT IN THE RECRUITMENT OF IMMUNE CELLS, THUS CREATING A MUTUAL CROSSTALK. THE RECIPROCAL SIGNALING BETWEEN THE TUMOR CELLS AND THE IMMUNE CELLS CREATES AND MAINTAINS A SUCCESSFUL TUMOR NICHE. MANY INFLAMMATORY FACTORS ARE REGULATED BY EPIGENETIC MECHANISMS INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS. IN PARTICULAR, DNA AND HISTONE METHYLATION ARE CRUCIAL FORMS OF TRANSCRIPTIONAL REGULATION AND ABERRANT METHYLATION HAS BEEN ASSOCIATED WITH DEREGULATED GENE EXPRESSION IN ONCOGENESIS. SUCH DEREGULATIONS HAVE BEEN REPORTED IN BOTH SOLID TUMORS AND HEMATOLOGICAL MALIGNANCIES. WITH TECHNOLOGICAL ADVANCEMENTS TO STUDY GENOME-WIDE EPIGENETIC LANDSCAPES, IT IS NOW POSSIBLE TO IDENTIFY MOLECULAR MECHANISMS UNDERLYING ALTERED INFLAMMATORY PROFILES IN CANCER. IN THIS REVIEW, WE DISCUSS THE ROLE OF DNA AND HISTONE METHYLATION IN REGULATION OF INFLAMMATORY PATHWAYS IN HUMAN CANCERS AND REVIEW THE MERITS AND CHALLENGES OF TARGETING INFLAMMATORY MEDIATORS AS WELL AS EPIGENETIC REGULATORS IN CANCER. 2021 15 2535 26 EPIGENETICS IN CHRONIC LYMPHOCYTIC LEUKEMIA. ENORMOUS EVIDENCE HAS ACCUMULATED IN THE PAST DECADES THAT ESTABLISHES THE IMPORTANCE OF EPIGENETIC MODIFICATIONS IN CANCER AND HAS RESULTED IN SHIFTING THE FOCUS FROM ENTIRELY GENETIC-BASED STUDIES TO INTEGRATED STUDIES INVOLVING BOTH GENETIC AND EPIGENETIC ALTERATIONS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS ONE SUCH EXAMPLE WHERE STUDIES INVOLVING EPIGENETIC ABERRATIONS HAVE ACCELERATED THE SEARCH FOR AFFECTED GENES, WHICH WAS INITIALLY RESTRICTED TO COMMONLY DELETED CHROMOSOMAL REGIONS. MANY NOVEL GENES THAT ARE EPIGENETICALLY SILENCED IN CLL HAVE BEEN IDENTIFIED. ADVANCES IN THE UNDERSTANDING OF POST-TRANSLATIONAL HISTONE MODIFICATIONS AND DNA METHYLATION IN NORMAL AND IN CLL CELLS HAVE PROVEN TO BE EXTREMELY BENEFICIAL IN FINDING POWERFUL DIAGNOSTIC MARKERS, AS WELL AS IN EXPLORING NOVEL THERAPIES. AT PRESENT, THE FIELD OF EPIGENETICS IS AT AN EVOLVING STAGE, BUT THERE IS NO DOUBT THAT FURTHER UNRAVELING OF ITS CAUSE AND EFFECTS IN TRANSFORMED CELLS WILL BRING A NEW REVOLUTION IN CANCER THERAPEUTICS. 2006 16 2033 26 EPIGENETIC CHANGES IN SOLID AND HEMATOPOIETIC TUMORS. THERE ARE THREE CONNECTED MOLECULAR MECHANISMS OF EPIGENETIC CELLULAR MEMORY IN MAMMALIAN CELLS: DNA METHYLATION, HISTONE MODIFICATIONS, AND RNA INTERFERENCE. THE FIRST TWO HAVE NOW BEEN FIRMLY LINKED TO NEOPLASTIC TRANSFORMATION. HYPERMETHYLATION OF CPG-RICH PROMOTERS TRIGGERS LOCAL HISTONE CODE MODIFICATIONS RESULTING IN A CELLULAR CAMOUFLAGE MECHANISM THAT SEQUESTERS GENE PROMOTERS AWAY FROM TRANSCRIPTION FACTORS AND RESULTS IN STABLE SILENCING. THIS NORMALLY RESTRICTED MECHANISM IS UBIQUITOUSLY USED IN CANCER TO SILENCE HUNDREDS OF GENES, AMONG WHICH SOME CRITICALLY CONTRIBUTE TO THE NEOPLASTIC PHENOTYPE. VIRTUALLY EVERY PATHWAY IMPORTANT TO CANCER FORMATION IS AFFECTED BY THIS PROCESS. METHYLATION PROFILING OF HUMAN CANCERS REVEALS TISSUE-SPECIFIC EPIGENETIC SIGNATURES, AS WELL AS TUMOR-SPECIFIC SIGNATURES, REFLECTING IN PARTICULAR THE PRESENCE OF EPIGENETIC INSTABILITY IN A SUBSET OF CANCERS AFFECTED BY THE CPG ISLAND METHYLATOR PHENOTYPE. GENERALLY, METHYLATION PATTERNS CAN BE TRACED TO A TISSUE-SPECIFIC, PROLIFERATION-DEPENDENT ACCUMULATION OF ABERRANT PROMOTER METHYLATION IN AGING TISSUES, A PROCESS THAT CAN BE ACCELERATED BY CHRONIC INFLAMMATION AND LESS WELL-DEFINED MECHANISMS INCLUDING, POSSIBLY, DIET AND GENETIC PREDISPOSITION. THE EPIGENETIC MACHINERY CAN ALSO BE ALTERED IN CANCER BY SPECIFIC LESIONS IN EPIGENETIC EFFECTOR GENES, OR BY ABERRANT RECRUITMENT OF THESE GENES BY MUTANT TRANSCRIPTION FACTORS AND COACTIVATORS. EPIGENETIC PATTERNS ARE PROVING CLINICALLY USEFUL IN HUMAN ONCOLOGY VIA RISK ASSESSMENT, EARLY DETECTION, AND PROGNOSTIC CLASSIFICATION. PHARMACOLOGIC MANIPULATION OF THESE PATTERNS-EPIGENETIC THERAPY-IS ALSO POISED TO CHANGE THE WAY WE TREAT CANCER IN THE CLINIC. 2005 17 3565 32 IMPACT OF GENETIC POLYMORPHISMS AND BIOMARKERS ON THE EFFECTIVENESS AND TOXICITY OF TREATMENT OF CHRONIC MYELOID LEUKEMIA AND ACUTE MYELOID LEUKEMIA. MOST MALIGNANT HEMATOLOGICAL DISEASES ARE GENERALLY A CONSEQUENCE OF ACQUIRED MUTATIONS OR REARRANGEMENTS IN CELL REPLICATION PROCESSES. ACUTE MYELOID LEUKEMIA (AML) IS A CLINICALLY AND MOLECULARLY HETEROGENEOUS DISEASE THAT RESULTS FROM ACQUIRED GENETIC AND EPIGENETIC ALTERATIONS IN HEMATOPOIETIC PROGENITOR CELLS. DESPITE THE ADVANCES MADE IN UNDERSTANDING THE PATHOGENESIS OF THIS DISEASE, THE OVERALL SURVIVAL OF PATIENTS REMAINS VERY LOW DUE TO THE HIGH RELAPSE RATE. PHARMACOGENETICS AND MASSIVE SEQUENCING STUDIES HAVE ALLOWED THE IDENTIFICATION OF NEW RECURRENT MUTATIONS WITH SIGNIFICANT PROGNOSTIC IMPACT IN AML; FURTHERMORE, IT SEEMS LIKELY THAT WHOLE GENOME SEQUENCING WILL SOON BECOME A STANDARD DIAGNOSTIC TEST, WHICH WILL ALLOW THE MOLECULAR DIAGNOSIS OF PATIENTS. THEREFORE, IT IS NECESSARY TO DEVELOP MOLECULAR TARGETS THAT OPEN NEW THERAPEUTIC PERSPECTIVES AND ALLOW INDIVIDUALIZED TREATMENT OF PATIENTS WITH THIS AGGRESSIVE DISEASE. CHRONIC MYELOID LEUKEMIA (CML) IS THE FIRST NEOPLASTIC DISEASE FOR WHICH A CHARACTERISTIC GENETIC ALTERATION WAS DESCRIBED. IT HAS, BY DEFINITION, A GENETIC MARKER, THE BCR::ABL1 REARRANGEMENT, AS A CONSEQUENCE OF THE T9;22(Q34;Q11) TRANSLOCATION. ITS STUDY IS ESSENTIAL FOR THE DIAGNOSIS OF THIS ENTITY AND ALSO FOR MONITORING THE RESPONSE TO TREATMENT. DRUGS KNOWN AS TYROSINE KINASE INHIBITORS (TKIS) THAT TARGET THE BCR::ABL1 PROTEIN (ORAL TARGETED THERAPY) ARE THE CONVENTIONAL TREATMENT OF CML, REPRESENTING A CHANGE OF PARADIGM IN THE MANAGEMENT OF ONCOHEMATOLOGICAL PATIENTS. 2022 18 6263 32 THE MULTIPLE WAYS WNT SIGNALING CONTRIBUTES TO ACUTE LEUKEMIA PATHOGENESIS. WNT PROTEINS CONSTITUTE A VERY CONSERVED FAMILY OF SECRETED GLYCOPROTEINS THAT ACT AS SHORT-RANGE LIGANDS FOR SIGNALING WITH CRITICAL ROLES IN HEMATOPOIESIS, EMBRYONIC DEVELOPMENT, AND TISSUE HOMEOSTASIS. THESE PROTEINS TRANSDUCE SIGNALS VIA THE CANONICAL PATHWAY, WHICH IS BETA-CATENIN-MEDIATED AND BETTER-CHARACTERIZED, OR VIA MORE DIVERSE NONCANONICAL PATHWAYS THAT ARE BETA-CATENIN INDEPENDENT AND COMPRISE THE PLANAR CELL POLARITY (PCP) PATHWAY AND THE WNT/CA(++) PATHWAYS. SEVERAL PROTEINS REGULATE WNT SIGNALING THROUGH A VARIETY OF SOPHISTICATED MECHANISMS. DISORDERS WITHIN THE PATHWAY CAN CONTRIBUTE TO VARIOUS HUMAN DISEASES, AND THE DYSREGULATION OF WNT PATHWAYS BY DIFFERENT MOLECULAR MECHANISMS IS IMPLICATED IN THE PATHOGENESIS OF MANY TYPES OF CANCER, INCLUDING THE HEMATOLOGICAL MALIGNANCIES. THE TYPES OF LEUKEMIA DIFFER CONSIDERABLY AND CAN BE SUBDIVIDED INTO CHRONIC, MYELOID OR LYMPHOCYTIC, AND ACUTE, MYELOID OR LYMPHOCYTIC, LEUKEMIA, ACCORDING TO THE DIFFERENTIATION STAGE OF THE PREDOMINANT CELLS, THE PROGENITOR LINEAGE, THE DIAGNOSTIC AGE STRATA, AND THE SPECIFIC MOLECULAR DRIVERS BEHIND THEIR DEVELOPMENT. HERE, WE REVIEW THE ROLE OF WNT SIGNALING IN NORMAL HEMATOPOIESIS AND DISCUSS IN DETAIL THE MULTIPLE WAYS CANONICAL WNT SIGNALING CAN BE DYSREGULATED IN ACUTE LEUKEMIA, INCLUDING ALTERATIONS IN GENE EXPRESSION AND PROTEIN LEVELS, EPIGENETIC REGULATION, AND MUTATIONS. FURTHERMORE, WE HIGHLIGHT THE DIFFERENT IMPACTS OF THESE ALTERATIONS, CONSIDERING THE DISTINCT FORMS OF THE DISEASE, AND THE THERAPEUTIC POTENTIAL OF TARGETING WNT SIGNALING. 2020 19 4320 27 MICRORNAS IN CHRONIC LYMPHOCYTIC LEUKEMIA: AN OLD DISEASE WITH NEW GENETIC INSIGHTS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS THE MOST COMMON LEUKEMIA AMONG ADULT POPULATION IN WESTERN COUNTRY. IN THE LAST DECADE, SEVERAL FINDINGS HAVE SUBSTANTIALLY REVOLUTIONIZED THE OLD CONCEPT THAT CLL IS A DISEASE ORIGINATING FROM MATURE, NOT-DIVIDING CELL WITH INDOLENT CLINICAL COURSE. NOTABLY, NEXT GENERATION SEQUENCING (NGS) HAS CONTRIBUTED TO DEEPEN THE KNOWLEDGE OF THE CELLULAR NETWORKS THAT IMPLY THE ONSET AND THE PROGRESSION OF CLL. AMONG GENETIC ABERRATIONS THAT ARE RECURRENTLY OBSERVED IN B-CELLS FROM PATIENTS WITH CLL, MICRORNA DEREGULATION REPRESENTED THE FIRST EPIGENETIC MECHANISM THAT HAS BEEN IDENTIFIED. THROUGH EPIGENETIC MECHANISM THEY CAN MODULATE GENE EXPRESSION AND INTERFERE WITH CELLULAR PATHWAYS THAT ARE INVOLVED IN CELL CYCLE, APOPTOSIS AND B-CELL RECEPTOR (BCR) ACTIVATION. ALTHOUGH FEW STUDIES HAVE SHOWN THE PROGNOSTIC AND PREDICTIVE VALUE OF MICRORNA EXPRESSION LEVELS, THEIR VALIDATION WITHIN PROSPECTIVE CLINICAL TRIALS IS WARRANTED. 2016 20 2025 32 EPIGENETIC CHANGES DURING DISEASE PROGRESSION IN A MURINE MODEL OF HUMAN CHRONIC LYMPHOCYTIC LEUKEMIA. EPIGENETIC ALTERATIONS, INCLUDING GAIN OR LOSS OF DNA METHYLATION, ARE A HALLMARK OF NEARLY EVERY MALIGNANCY. CHANGES IN DNA METHYLATION CAN IMPACT EXPRESSION OF CANCER-RELATED GENES INCLUDING APOPTOSIS REGULATORS AND TUMOR SUPPRESSORS. BECAUSE SUCH EPIGENETIC CHANGES ARE REVERSIBLE, THEY ARE BEING AGGRESSIVELY INVESTIGATED AS POTENTIAL THERAPEUTIC TARGETS. HERE WE USE THE EMU-TCL1 TRANSGENIC MOUSE MODEL OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) TO DETERMINE THE TIMING AND PATTERNS OF ABERRANT DNA METHYLATION, AND TO INVESTIGATE THE MECHANISMS THAT LEAD TO ABERRANT DNA METHYLATION. WE SHOW THAT CLL CELLS FROM EMU-TCL1 MICE AT VARIOUS STAGES RECAPITULATE EPIGENETIC ALTERATIONS SEEN IN HUMAN CLL. ABERRANT METHYLATION OF PROMOTER SEQUENCES IS OBSERVED AS EARLY AS 3 MONTHS OF AGE IN THESE ANIMALS, WELL BEFORE DISEASE ONSET. ABNORMALLY METHYLATED PROMOTER REGIONS INCLUDE BINDING SITES FOR THE TRANSCRIPTION FACTOR FOXD3. WE SHOW THAT LOSS OF FOXD3 EXPRESSION DUE TO AN NF-KAPPAB P50/P50:HDAC1 REPRESSOR COMPLEX OCCURS IN TCL1-POSITIVE B CELLS BEFORE METHYLATION. THEREFORE, SPECIFIC TRANSCRIPTIONAL REPRESSION IS AN EARLY EVENT LEADING TO EPIGENETIC SILENCING OF TARGET GENES IN MURINE AND HUMAN CLL. THESE RESULTS PROVIDE STRONG RATIONALE FOR THE DEVELOPMENT OF STRATEGIES TO TARGET NF-KAPPAB COMPONENTS IN CLL AND POTENTIALLY OTHER B-CELL MALIGNANCIES. 2009